October 25, 2007

2,5-Dibromopyridine-4-carboxaldehyde

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In a round flask with a large egg-shaped stirbar, a solution of diisopropyl amine 3.1 g (4.2 mL; 30 mmol) in anh. THF (approx 140mL) under Ar was cooled to 0C, 2.5M BuLi solution in hexane 11 mL (27.5 mmol) was added over 5 min and the mixture was stirred on ice for additional 5 min and then cooled to -78C. To this LDA solution, an ice-cooled solution of 2,5-dibromopyridine 5.925 g (25 mmol) in anh THF (approx 50 mL) was slowly added via thin canula (gauge 18) along the flask wall over 20 min with vigorous stirring (at near-maximum speed). The flask and the canula were washed with additional anh THF (2x5mL). [Note 1] After the complete addition the mixture was stirred at -78C for extra 20 min. Anhydrous DMF 2.4 mL was then added drop-by drop over 6 min period, the mixture was then stirred for additional 30 min at -78C. The reaction was quenched by dropwise water addition (10mL), the cooling bath was replaced with ambient water bath and when the mixture warmed above 0 C additional water 90mL was added. The mixture was stirred at RT for 30 min during which time the color turned from purplish to yellow-brown. The reaction mixture was combined with hexane 100mL and sat NaCl 100mL in a separatory funnel and separated. The organic phase was washed twice with sat. NaHCO3, 2x150mL. The aqueous phases were re-extracted with ether 100mL. The combined organic extracts were dried (MgSO4) and evaporated. The residue was re-evaporated from benzene 60mL and dried on highvac. The obtained semi-solid residue was dissolved in refluxing cyclohexane 60mL, the solution was decanted and the remaining dark gummy insoluble residue was re-extracted with some additional cyclohexane (2x10mL) at reflux. The combined cyclohexane solutions were allowed to cool down to RT, after 1 hour the cloudy solution was filtered through a medium-porosity Buchner funnel (to remove a small amount of insoluble sticky impurities; the filtration funnel was washed with additional cyclohexane) and the filtrates were evaporated.

The obtained solid residue was re-crystallized from cyclohexane 25mL (reflux to RT, overnight). The supernatants were decanted and the crystallized product was suspended in a mixture cyclohexane-hexane 1:1 (approx 10mL), filtered, washed with some additional 1:1 cyhex-hex mixture and dried on highvac to yield 3.398g of pure product. The supernatants were combined with the washings and placed in refrigerator (+2C) overnight. The supernatants were decanted from the crystals, the obtained second fraction was suspended in 1:1 cyhex-hexane mixture, filtered, covered with a small volume (4 mL) of cyclohexane on a Buchner funnel and crushed and stirred with spatula (to remove some sticky oil adhering to the crystals), then filtered and washed again with some 1:1 cyhex-hex mixture and then dried – to provide additional 633mg of pure product.
Combined Y = 4.031g (61% th) of a light orange-tan crystalline solid

Note 1: 5-halo-4-pyridyl lithium species are very sensitive, they decompose readily above -78C and they also tend to equilibrate to isomeric 3-pyridyl lithiums. It is important to avoid overheating when adding the pyridine to the LDA solution. Efficient stirring aids the heat transfer. The halopyridine substrate solution should be added slowly, pre-cooled. As 2,5-dibromopyridine is poorly soluble in THF at low temperatures, it was pre-cooled only to 0C. (Some dibromopyridine precipitation occurs on the flask wall during the canula addition but the material is washed down into the reaction mixture during the canula wash with additional THF.)

Credit: Lithiation of 2,5-dibromopyridine in the 4 position is not described in the literature but the procedure is based on Schlosser work. I am grateful to my colleague, Par, whose advice and pyridines I took.

Not much, I run this particular experiment only once – but I did few similar ones before, on related chloro/fluoropyridines. The halopyridine aldehydes are quite reactive and tend to crap up on silica so the idea was to purify by re-crystallization. (Also I may need to scale up the procedure eventually so I am trying to avoid the column.) There are some impurities that oil out during recrystallization so I had to try to remove those first. I have no idea what they are – my guess is something diisopropylamine/DMF-related. The workup has to be done such that the secondary amines are removed, they tend to carry over with the pyridine aldehydes and complicate the purification – bicarbonate is a suitable mildly-basic buffer that won’t support the iminium formation and it extracts the secondary alkylamines. And so on.

I don’t know. But the general rule is that LDA does not exchange halogen for Li; it deprotonates.

The interesting thing is that when you metalate 2,5-dichloropyridine with tert-butyl lithium (1 eq) in diethyl ether at -78C, you get lithiation into the 6 position. Schlosser mentions the preparation of 2,5-dichloropyridine-6-carboxaldehyde in 80% Y, I got only 51%Y after recrystallization (but his published experimental note is not terribly detailed, I had a problem with extensive starting material precipitation and I did the experiment only once).

I must correct my comment about the stability of halopyridine aldehydes on silica: I just finished a purification of 2-bromo-5-fluoropyridine-4-carboxaldehyde on silica column (EtOAc 0 to 25% gradient in hexane) and got 81% yield of purified product. I used the same procedure as for 2,5-dibromopyridine-4-carboxaldehyde but with 2-Br-5-F-pyridine as a starting material (added pre-cooled to -78C) on 40 mmol scale with identical reactant ratios but slightly more concentrated reaction mix (THF: 150mL for LDA plus 50mL to dissolve the starting material). The product refused to crystallize crude so I had to column it and it worked without complication.

Hey milkshake, what happens if you only have a halo substituent in the 2 position? Do you get competition for deprotonation at the 4/6 position now, or does it still only deprotonate at 4? This is very relevant actually. Thanks for posting it!

You should check papers from Schlosser from the last 8-10 years – he has done a lot of work on halopyridines.

I think the halogen works as a directing group. So if you have 2-halo you could get lithiation into the 3 position, depending on the base. But 3-pyridyl lithiums can readily equilibrate to 4-pyridyl lithiums. More bulky base like LiTMP or LiN(TMS)2 could favor other positions. I really don’t know.

Sorry, forgot to leave a message here after reading lots of papers on the matter and trying some other reactions. Anyways, I looked into it and read a Schlosser review, but it looks like it’s no dice for my particular problem. At least not in a very direct sense where it doesn’t take more than five steps to make what I want using that type of chemistry. I’ll have to find another way.